Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney.
Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney.
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DOI：
10.1016/j.matbio.2017.12.002
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发表时间：
2017-12
期刊：
影响因子：
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通讯作者：
M. Nastase;Jinyang Zeng-Brouwers;J. Beckmann;Claudia Tredup;U. Christen;H. Radeke;M. Wygrecka;L. Sc
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文献类型：
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作者：
M. Nastase;Jinyang Zeng-Brouwers;J. Beckmann;Claudia Tredup;U. Christen;H. Radeke;M. Wygrecka;L. Sc
Th1和Th17细胞是辅助性T细胞(Th)亚群，是肾脏纤维化的关键诱因。然而，它们重新进入肾脏的分子机制还不是很清楚。在这里，我们证明了Biglycan，一种细胞外基质的蛋白多糖，以其可溶的形式作为危险信号，自主地刺激巨噬细胞产生Th1和Th17趋化物质CXCL10和CCL20。在干扰素γ存在的情况下，Biglycan协同刺激CXCL9。在缺乏TLR2、TLR4及其接头分子MyD88或TRIF的巨噬细胞中，我们确定了双聚糖依赖的Th1/17趋化作用的高度选择性机制。因此，CXCR3阳性的Th1和Th17细胞共同的趋化物质CXCL9和CXCL10的表达是以Biglycan-TLR4/TRIF依赖的方式触发的。相反，Biglycan以TLR2/4/MyD88依赖的方式诱导CCL20趋化因子的产生，负责CCR6阳性的Th17细胞的募集。重要的是，在糖尿病和狼疮性肾炎的发病中，我们提供了在缺乏或过度表达可溶性双聚糖的小鼠中依赖双糖依赖的Th1和Th17细胞的募集，干扰素γ和IL-17的产生，以及蛋白尿的发展的证据。此外，通过基因消融CxCl10，我们在体内显示了这种趋化因子参与了Th1和Th17细胞在肾脏中的二聚糖依赖的募集。糖尿病肾病和狼疮性肾炎患者血浆Biglycan水平与CXCL10/CXCL9水平呈正相关。综上所述，我们确认Biglycan是Th1和Th17细胞募集到肾脏的新的触发因素，我们推测干扰Biglycan/TLR/TRIF/MyD88-信号可能为肾脏纤维化提供新的治疗途径。
Th1 and Th17 cells, T helper (Th) subtypes, are key inducers of renal fibrosis. The molecular mechanisms of their recruitment into the kidney, however, are not well understood. Here, we show that biglycan, a proteoglycan of the extracellular matrix, acting in its soluble form as a danger signal, stimulates autonomously the production of Th1 and Th17 chemoattractants CXCL10 and CCL20 in macrophages. In the presence of IFNγ, biglycan synergistically stimulates CXCL9. In macrophages deficient for TLR2, TLR4, and their adaptor molecules MyD88 or TRIF, we identified highly selective mechanisms of biglycan-dependent Th1/17 chemoattraction. Thus, the expression of CXCL9 and CXCL10, common chemoattractants for CXCR3-positive Th1 and Th17 cells, is triggered in a biglycan-TLR4/TRIF-dependent manner. By contrast, biglycan induces CCL20 chemokine production, responsible for CCR6-positive Th17 cell recruitment, in a TLR2/4/MyD88-dependent manner. Importantly, at the onset of diabetes mellitus and lupus nephritis we provide evidence for biglycan-dependent recruitment of Th1 and Th17 cells, IFNγ and IL-17 production, and development of albuminuria in mice lacking or overexpressing soluble biglycan. Furthermore, by genetic ablation ofCxcl10we showed in vivo involvement of this chemokine in biglycan-dependent recruitment of Th1 and Th17 cells into the kidney. Finally, a positive correlation of biglycan and CXCL10/CXCL9 levels was detected in plasma from patients with diabetic nephropathy and lupus nephritis. Taken together, we identified biglycan as a novel trigger of Th1 and Th17 cell recruitment into the kidney and we postulate that interfering with biglycan/TLR/TRIF/MyD88-signaling might provide novel therapeutic avenues for renal fibrosis.